1) Improving treatment of cryptococcal meningitis. Cryptococcus neoformans is the most common cause of non-viral meningitis in the U.S. and the disease continues to have an attributable mortality of approximately 30% despite therapy. We have recruited approximately 150 patients with both meningoencephalitis and pulmonary disease. The protocol utilizes the latest in immunological and genetic methods and is divided in two parts: 1) to characterize and apply novel therapeutics to the acute phase of the disease to improve outcomes and 2) identify genetic and immunological risk factors involved in susceptibility to the disease during the convalescence phase. 1) In our last project period we identified a syndrome in cryptococcal infections in CM, a post-infectious inflammatory syndrome, (PIIRS), which results in a dysfunctional activated immune response within the brains of patients after microbiological control of the organism with standard therapies. Immunological profiling identified several biomarkers of PIIRS. Within the restricted confines of the skull, this excessive immune activity causes the brain to swell and become dysfunctional, resulting in coma and death. In collaboration with NINDS (B. Bielekova, O. Khan and A. Nath) and the neurosurgical service of the NIH clinical center (P. Chittiboina), we have extended these studies by developing novel treatment strategies to treat patients referred to the NIH clinical center. This has resulted in reducing the mortality approximately 10-fold to less than 2%. 2) Host susceptibility to cryptococcal disease in previously healthy individuals. a) Autoantibody to host cytokines: Previously, in collaboration with S. Browne of LCID, we had identified patients with C. gattii, a related form of Cryptococcus with an autoantibody to the macrophage stimulator granulocyte-monocyte stimulating factor, GM-CSF. We are presently studying the regulatory pathway of GM-CSF signaling and have found that autophagy plays a key role in concert with the macrophage inflammasome pathway, suggesting novel mechanisms for intervention. b) Genetic Defects: We have currently performed whole exome sequencing on 96 patients with CM disease are currently working up a number of novel mutations utilizing cellular studies and mouse models.